Antidepressant 1,1a,6,10b-tetrahydrodibenzo-[a,e]-cyclopropa-[c]-cyclohepten-6-substituted oximes

ABSTRACT

Antidepressant 1,1a,6,10b-tetrahydrodibenzo-[a,e]-cyclopropa-[c]-cyclohepten-6-substi tuted oximes and their pharmaceutically suitable salts useful for alleviating depression in mammals.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division of application Ser. No. 616,483, filed Sept. 26,1975, now U.S. Pat. No. 3,960,956 which application is acontinuation-in-part of my copending application Ser. No. 525,877, filedNov. 21, 1974, now abandoned.

BACKGROUND

This invention relates to tetracyclic antidepressants,dibenzocycloheptenes with a nuclearly fused cyclopropyl moiety.

Dostert and Kyburz (U.S. Pat. No. 3,803,234) disclose N-(aminoalkyl orheterocyclic aminoalkyl) dibenzocycloheptene imine derivatives.

Judd (U.S. Pat. No. 3,349,128) discloses dibenzocycloheptenes having anaminoalkylene ether attached to the imino nitrogen but without thenuclear fused cyclopropyl moiety.

The following patents relate to compounds with the same basic carbonskeleton but different substituents in the 6-position: Coyne (U.S. Pat.No. 3,574,199), aminoalkyl or aminoalkylidene; Coyne (U.S. Pat. No.3,547,933 and U.S. Pat. No. 3,658,908), hydroxy or lower alkanoyloxy andvarious aminoalkyl groups; Remy (U.S. Pat. No. 3,475,438), N-alkylpiperidine; Uyeda (Belgian Pat. No. 805,433 and French Pat. No.2,201,089), alkylated imine.

Mental illness encompasses both psychoses and neuroses. Symptomsrequiring treatment include depression, anxiety, agitation, andhallucinations. Among the drugs used particularly for treatment of bothreactive and endogenous depressions are monoamine oxidase (MAO)inhibitors, such as iproniazide, tranylcypromine, nialamide, phenelzine,and pargyline, and the non-MA0-inhibiting tricyclic aromaticdibenzazepines, such as imipramine, and dibenzocycloheptenes such asamitriptyline.

All of these drugs have adverse side effects that limit theirusefulness. MAO inhibitors may benefit milder forms of depression, butthe risk of serious toxic effects is a strong argument against theiruse. They may cause liver damage and acute hypertension, especially ifgiven in conjunction with cheese, bananas, or other amine-containingfoods. The MAO inhibitors may also cause tremors, insomnia,hyperhydrosis, agitation, hypermanic behavior, confusion,hallucinations, convulsions and orthostatic hypotension. They frequentlycause dizziness, vertigo, headache, inhibition of ejaculation,difficulty in urination, weakness, fatigue, dry mouth, constipation andblurred vision.

Imipramine may cause blurred vision, dryness of mouth, constipation,urinary retention, orthostatic hypotension, respiration depression,myocardial infarction, and congestive heart failure. Similardifficulties are experienced with amitriptyline.

There is a continuing need for psychotherapeutic agents that have fewerside effects than the drugs in use today; also for psychotherapeuticagents that have different modes of action than presently used agents,since none of these is completely effective.

The present invention results from efforts to develop new, safe, andeffective psychotherapeutic compounds with minimal side effects.

SUMMARY

According to this invention there is provided novel compounds of formulaI and their pharmaceutically suitable salts, processes for theirmanufacture, compositions containing them, and methods of using them toalleviate depression in mammals. ##STR1## where X or Y = H, F, Cl, Br,C₁₋ C₄ alkyl, C₁ - C₄ alkoxy, CF₃, CH₃ S, CH₃ SO₂, SO₂ N(CH₃)₂, providedthat one is H;

Z = c₂ -- c₃ alkylene;

R₁ and R₂ independently = H, C₁₋ C₄ alkyl, or together can form a ringwith N; ##STR2## in which W can be --(CH₂)₄ --, --(CH₂) or

--(CH₂)₂ O(CH₂)₂₋₋.

DETAILED DESCRIPTION Preferred Compounds

Compounds preferred because of their high degree of activity are thosein which R₁ and R₂ = H or CH₃.

More preferred are those in which X and Y = H, Z = ethylene, and R₁ andR₂ = H or CH₃.

The compound most preferred is that in which X and Y = H, Z = ethylene,and R₁ and R₂ = H.

Pharmaceutical Salts

Pharmaceutically suitable acid addition salts of these compounds includethose made with physiologically acceptable acids that are known in theart; such salts include hydrochloride, sulfate, nitrate, phosphate,citrate, tartrate, maleate and the like.

Synthesis

Compounds of this invention are prepared as shown in the followinggeneral reaction scheme. ##STR3## in which R¹, R², X, Y and Z are aspreviously defined and M is an alkali metal.

Another method of preparing some of the compounds involves reaction ofthe oxime of a dibenzocyclopropacycloheptene in the form of its alkalimetal salt, e.g., sodium, with ethylene oxide to give the corresponding0-β-hydroxyethyloxime, which is converted to its tosylate by reactionwith p-toluenesulfonylchloride. The tosylate reacts with a hydrogenbearing amine to give the aminoalkyloximes as shown by the following##STR4##

Another method for preparation of the 0-β-hydroxyethyloxime ofdibenzocyclopropacycloheptene is the treatment of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onedimethylketal with carboxymethoxylamine hemihydrochloride to give the0-α-carboxymethyloxime derivative. Reduction of this acid withborane-THF complex or borane dimethylsulfide complex gives the0-β-hydroxyethyloxime as shown by the following: ##STR5##

The nuclearly substituted1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onesused as precursors can be prepared by treating5H-dibenzo[a,d]-cyclohepten-5-ones under anhydrous conditions withsodium methoxide and ethyltrichloroacetate or heating at reflux abenzene solution of the ketone and phenyltrichloromethyl mercury to form1,1-dichloro-1,1a-6,10-b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onesof the general formula: ##STR6## and subsequently reducing thedichloroketone to the corresponding carbinol by treatment in solutionwith sodium borohydride to produce the alcohol. The gem chlorines andany halogen on the benzene rings can be replaced with hydrogen bytreatments of the dichloroalcohol with lithium and tert.-butanolfollowed by oxidation with chromium trioxide in sulfuric acid orchromium trioxide in pyridine to form the precursors (II).

The basic starting material, 5H-dibenzo[a,d]cyclohepten-5-one iscommercially available. Synthesis of the benzo-substituted analogs canbe carried out by adaptation of the synthesis procedures shown in:

A.c. cope et al., J. Am. Chem. Soc. 73, 1673 (1951)

W. treibs et al., Ber. 84, 671 (1951)

S. o. winthrop et al., J. Org. Chem. 27, 230 (1962).

Another method of preparing the precursor compounds is addition ofdichlorocarbene to the commercially available5H-dibenzo[a,d]cyclohepten-5one by the method described in U.S. Pat. No.3,547,933 to give1,1-dichloro-1,1a,6,-10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclophepten-6-one.Treatment of this dichloroketone with POCl₃ -PCl₅ followed by sodiummethoxide in methanol or triethylamine in methanol gives1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onedimethylketal. Both chlorine atoms can be replaced with hydrogen byreaction with lithium hydride-triethylborane (lithiumtriethylborohydride) in hexamethylphosphoramide to give1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one-dimethylketal.Treatment of this ketal with acid yields1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one.Reaction of this ketone with hydroxylamine gives the1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime.An advantage of this synthesis is retention of substituents, such ashalogen, on one or more of the benzene rings.

Another method of preparing the precursor compounds is by treating therespective 5-H-dibenzo[a,d]cyclohepten-5-ones with bromoform and base¹or heating at reflux a benzene solution of the ketone andphenyltribromomethyl mercury to form the respective1,1-dibromo-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onesof the general formula: ##STR7## Treatment of this dibromoketone withPOCl₃ - PCl₅ followed by triethylamine in methanol gives1,1-dibromo-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onedimethylketal. Replacement of both of the bromine atoms with hydrogen iseffected by reflux with lithium aluminum hydride in tetrahydrofuran, orlithium in tert-butanol, or lithium hydride-triethylbroane (lithiumtriethylborohydride) in hexamethylphosphoramide to give1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onedimethylketal. Treatment of this ketal with hydroxylamine hydrochloridein pyridine gives the1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime.

The oxime is readily formed by treatment of the 6-oxo compound withhydroxylamine, generally at 50°-125° for 10-24 hours. in the presence ofa tertiary amine such as pyridine as illustrated by Example 1A below.

Another method of preparing the precursor1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime isby the reaction of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onedimethylketal with hydroxylamine hydrochloride in pyridine asillustrated by Example 1c. ##STR8##

Substituted oximes are prepared from the oxime by formation of an alkalimetal salt, suitably by reaction with a molar amount of an alkali metalhydride, such as readily available sodium hydride. The alkali metal saltis then reacted with a halide, Hal--ZNR¹ R², in an inert, anhydroussolvent, such as hexamethylphosphoramide, generally at 10°-50° for a fewminutes to an hour or more. The inorganic alkali metal halide is removedby washing, and the O-substituted oxime separated and purified.

The O-substituted oximes can also be prepared by treating the ketone IIor its dimethylketal derivative with the appropriately O-substitutedhydroxylamine hydrochlorides in pyridine as shown: ##STR9##

The compounds of this invention have a basic group, i.e., an amino orsubstituted amino group, that is 2-4 carbons removed from the oxygenether linkage. This amino group is salt forming and facilitates thepreparation of aqueous solutions for pharmaceutical use.

In addition, unlike the corresponding imines, these compounds havesuperior stability under hydrolytic conditions. For example, a solutionof 0.6 g ofN-(2-methylaminoethyl)-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-iminein 20 ml of 0.5M hydrochloric acid was stirred at 25° for 20 hrs. Thesolution was cooled and 10 ml of 10% sodium hydroxide solution wasadded, and the oil was twice extracted with a solution of 25% methylenechloride in ether. The combined organic extracts were thoroughly washedwith saturated brine, dried and solvent removed. The NMR spectrum of theresidue (0.5 g) indicated about 40% decomposition of the imine to theketone occurred.

Following the same procedure1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(methylamino)ethyl]oxime showed no detectable decomposition. Thisstability to hydrolysis is advantageous in preparation, storage, and useof pharmaceutical dosage forms.

In the following illustrative examples all parts are by weight andtemperatures are centigrade unless stated to be otherwise.

EXAMPLE 1 A.1,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one Oxime##STR10##

A solution of 6.6 g (0.03 mole) of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one, 8.4 g(0.12 mole) of hydroxylamine hydrochloride in 120 ml of pyridine washeld at reflux for 18.5 hrs. The solvent was evaporated under reducedpressure and the residue was dissolved with a mixture of water andmethylene chloride. The layers were separated and the organic layer wasin turn washed with 10% hydrochloric acid, and saturated brine, driedand solvent evaporated to give 7.4 g of crude1,a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime, mp201° (ex. MeOH, dried at 110°/0.1 mm). The NMR spectrum in CDCl₃-DMSO-d₆ : a singlet at δ10.9 (1H), multiplet at 6.9-7.6 (8H), multipletat 2.1-2.6 (2H) and multiplet at 1.3-1.8 (2H). Anal. Calcd. for C₁₆ H₁₃NO: C, 81.46; H, 5.57; N, 5.95. Found: C, 81.48; H, 5.68; N, 6.08. Massspec.: Calcd. for C₁₆ H₁₃ NO: 235.0996. Found: 235.0997.

B. 1,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(dimethylamino)ethyl]oxime ##STR11##

A dispersion of 2.5 g of 50% sodium hydride in mineral oil (0.052 moleof NaH) was thoroughly washed with hexane. To the sodium hydride, asolution of 4.8 g (0,020 mole) of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime in80 ml of anhydrous hexamethylphosphoramide (HMPA) was added and themixture was stirred at 25° for 1 hr under nitrogen. To the oxime saltthus formed was added 3.8 g (0.026 mole) of anhydrous2-dimethylaminoethylchloride hydrochloride and the mixture was stirredat 25° for 72 hrs. The reaction was quenched by the careful addition of40 ml of water, then the mixture was poured into excess water. The oilwas extracted twice with ether and the combined organic layers wereextracted twice with 50 ml of 10% hydrochloric acid. The acidic solutionwas thoroughly washed with ether, then treated with an excess of sodiumhydroxide solution. The oil was extracted with ether, washed withsaturated brine, dried and solvent removed. The residue was tituratedwith hexane to give 3.8 g of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(dimethylamino)ethyl]oxime, mp 69°-70° (from cyclohexane). The MNRspectrum (CDCl₃): multiplet at δ6.9-7.5 (8H), triplet (J=6Hz) at 4.3(2H), singlet at 2.2 superimposed on a multiplet at 2.2-3.9 (10H) and amultiplet at 1.3-1.9 (2H). Anal. Calcd. for C₂₀ H₂₂ N₂ O: C, 78.40; H,7.24; N, 9.14. Found: C,78.50; H, 7.01; N, 8,96 Mass spec.: Calcd. forC₂₀ H₂₂ N₂ O: 306.1731, Found: 306.1694.

C. 1,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclophepten-6-oneOxime

A solution of 1.5 g (5.6 moles) of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onedimethylketal, 2.5 g of hydroxylamine hydrochloride in 20 ml of pyridinewas held at reflux for 18 hr. The solvent was removed under reducedpressure and the residue was dissolved with a mixture of water andmethylene chloride. The layers were separated and the organic layer wasin turn washed with 10% hydrochloric acid, saturated sodium bicarbonatesolution and saturated brine, dried and solvent removed to give1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime.All of the physical properties were identical to those obtained byExample 1A. Note: The oxime forms a solvate with methanol.

EXAMPLE 21,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(dimethylamino)ethyl]oxime hydrochloride ##STR12##

1,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(dimethylamino)ethyl]oxime prepared as in Example 1 was dissolvedin ether and saturated with anhydrous hydrogen chloride. The precipitatewas filtered and thoroughly washed with ether. The product wasrecrystallized from acetonitrile, and dried at 100° (0.1 mm), mp169°-171°.

EXAMPLE 31,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(methylamino)ethyl]oxime ##STR13##

A dispersion of 1.5 g of 40% sodium hydride in mineral oil (0.025 moleof NaH) was thoroughly washed with hexane. To the sodium hydride, asolution of 2.4 g (0.010 mole) of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime in40 ml of dry hexamethylphosphoramide (HMPA) was added. The mixture wasstirred at 25° for 1 hr under nitrogen. To the oxime salt was added 1.7g (0.012 mole) of 2-methylaminoethylchloride hydrochloride and themixture was stirred at 25° for 16 hrs. The reaction was processes as inExample 1 to give 25 g of an oil. Chromatography on 25 g of silica gelwith ether as the eluent removed unreacted starting oxime. The crudeproduct was obtained with methanol-1% triethylamine as eluent. Flashdistillation (0.1μ, 180° bath) of the methanol fractions gave1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(methylamino)ethyl]oxime, MP 100°-101° C. NMR spectrum (CDCl₃):multiplet at δ6.8-7.5 (8H), triplet (J=6 Hz) at 4.2 (2H), tirplet (J=6Hz) at 2.8 (2H), singlet at 2.4 superimposed on a multiplet at 2.1-2.5(5H) and a multiplet at 1.3-1.8 (3 H). Mass. spec: Calcd. for C₁₉ H₂₀ N₂O: 292.1575; Found: 292.1546.

In Examples 4-11 reaction of1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oxime asits sodium salt with the recited alkylhalide as described in Example 1gives the indicated product.

EXAMPLE 41,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[3-(dimethylamino)propyl]oxime ##STR14##

This compound was prepared by the process of Example 1 using3-dimethylaminopropylchloride hydrochloride as the halogen aminocompound. Crystals obtained from its solution in cyclohexane showed amelting point of 83°-83.5°.

NMR spectrum (CDCl₃): multiplet at δ7.0-7.5 (8H), triplet (J=6 Hz) at4.2 (2H), singlet at 2.1 superimposed on a multiplet at 2.1-2.7 (10H)and multiplet at 1.3-2.1 (4H). Anal. Calcd. for C₂₁ H₂₄ N₂ O: C, 78.71;H, 7.55; N, 8.74. Found: C, 78.79; H, 7.42; N, 8.73. Mass Spec: Calcd.for C₂₁ H₂₅ N₂ O (M+1): 321.1995. Found: 321.2009.

EXAMPLE 51,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(morpholino)ethyl]oxime ##STR15##

This compound was prepared by the process of Example 1 usingN-(2-clorethyl)morpholine hydrochloride. Melting point 90°-91°,crystallized from isopropyl alcohol.

NMR (CDCl₃): multiplet at δ7.0-7.6 (8H), triplet (J=6 Hz) at 4.3 (2H),multiplet at 3.5-3.9 (4H), multiplet at 2.2-2.8 (8H) and multiplet at1.4-1.8 (2H).

EXAMPLE 61,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(pyrrolidino)ethyl]oxime ##STR16##

This compound was prepared using N-(2-chloroethyl)pyrrolidinehydrochloride. M.P. (ex. i-propyl alcohol) 96°-96.5°.

NMR (CDCl₃): multiplet at δ7.0-7.7 (8H), triplet (j=6 Hz) at 4.3 (2H),multiplet at 2.1-3.0 (8H) and multiplet at 1.4-1.9 (6H).

EXAMPLE 71,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-(2-aminoethyl)oxime ##STR17##

This compound was prepared using 2-chlorethylamine hydrochloride; mp133°-134° (ex iPrOH).

NMR (CDCl₃): multiplet at δ7.0-7.5 (8H), triplet (J=6 Hz) at 4.2 (2H),triplet (J=6 Hz) at 2.9 (2H), multiplet at 2.2-2.6(2H), multiplet at1.4-1.9 (2H) and singlet at 1.2 (2H, exchangeable with D₂ O).

EXAMPLE 81,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-(2-piperidinoethyl)oxime ##STR18##

This compound was prepared using N-(2-cloroethyl)piperidinehydrochloride; mp 75°-76° (ex. iPrOH).

NMR (CDCl₃): multiplet at δ7.0-7.6 (8H), triplet (J=6 Hz) at 4.3 (2H),multiplet at 2.2-2.9 (8H) and multiplet at 1.3-1.8 (8H).

EXAMPLE 91,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(diisopropylamino)ethyl]oxime ##STR19##

This compound was prepared using 2-diisopropylaminoethyl hydrochloride;mp 97°-98° (ex. iPrOH):

NMR (CDCl₃): multiplet at δ7.0-7.6 (8H), triplet (J=7 Hz) at 4.1 (2H),multiplet at 2.2-3.2 (6H), multiplet at 1.4-2.0 (2H) and doublet (J=7Hz) at 1.0 (12H).

EXAMPLE 101,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[3-(piperidino)propyl]oxime. ##STR20##

This compound was prepared using N-(3-chloropropyl) piperidinehydrochloride. It was flash distilled at 2μ (200° bath). NMR (CDCl₃):multiplet at δ6.9-7.5 (8H), triplet (j=6 Hz) at 4.2 (2H), and multipletat 1.1-2.7 (18H).

EXAMPLE 111,1a,6,10b-Tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one0-[2-(dimethylamino)ethyl]oxime ##STR21## Flash distilled at 0.1μ (160°bath).

NMR (CDCl₃): multiplet at δ7.0-7.5 (7H), triplet (J=6 Hz) at 4.3 (2H),singlet at 2.2 superimposed on a multiplet at 2.1-2.9 (10H) andmultiplet at 1.4-1.8 (2H).

The 4-clorodibenzocycloheptenone oxime was obtained by reaction of4-chloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-onewith hydroxylamine hydrochloride as described in Example 1A. The sodiumsalt was then reacted wit 2-dimethylaminoethylchloride hydrochloride asin Example 1B.

By the method described other nuclearly substituted1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-one oximes(Column 1 of Table I) react with 2-dimethylaminoethylchloridehydrochloride to yield the products in Column 2 of Table I.

                                      TABLE I                                     __________________________________________________________________________    Example   Starting Oxime     Substituted Oxime                                __________________________________________________________________________    a.   4-Bromo-1,1a,6,10b-tetrahydro-                                                                   4-Bromo-1,1a,6,10b-tetrahydrodi-                           dibenzo[a,e]cyclopropa[c] cyclo-                                                                 benzo[a,e]cyclopropa[c]cyclohepten-                        hepten-6-one oxime 6-one 0-[2-(dimethylamino)ethyl]-                                             oxime                                                 b.   4-Fluoro-1,1a,6,10b-tetrahydro-                                                                  4-Fluoro-1,1a,6,10b-tetrahydro-                            dibenzo[a,e]cyclopropa[c]cyclo-                                                                  dibenzo[a,e]cyclopropa[c]cyclo-                            hepten-6-one oxime hepten-6-one 0-[2-(dimethylamino)-                                            ethyl]oxime                                           c.   4-Trifluoromethyl-1,1a,6,10b-                                                                    4-Trifluoromethyl-1,1a,6-10b-tetra-                        tetrahydrodibenzo[a,e]cyclopropa-                                                                hydrodibenzo[a,e]cyclopropa[c]-                            [c]cyclohepten-6-one oxime                                                                       cyclohepten-6-one 0-[2-(dimethyl-                                             amino)ethyl]oxime                                     d.   4-Methyl-1,1a,6,10b-tetrahydro-                                                                  4-Methyl-1,1a,6,10b-tetrahydrodi-                          dibenzo[a,e]cyclopropa[c]cyclo-                                                                  benzo[a,e]cyclopropa[c]cyclohepten-                        hepten-6-one oxime 6-one 0-[2-(dimethylamino)ethyl]-                                             oxime                                                 e.   4-Methylsulfonyl-1,1a,6,10b-                                                                     4-Methylsulfonyl-1,1a,6,10b-tetra-                         tetrahydrodibenzo[a,e]cyclopro-                                                                  hydrodibenzo[a,e]cyclopropa[c]-                            pa[c] cyclohepten-6-one oxime                                                                    cyclohepten-6-one 0-[2-(dimethyl-                                             amino)ethyl]oxime                                     f.   2-Chloro-1,1a,6,10b-tetrahydro-                                                                  2-Chloro-1,1a,6,10b-tetrahydrodi-                          dibenzo[a,e]cyclopropa[c]cyclo-                                                                  benzo[a,e]cyclopropa[c]cyclohepten-                        hepten-6-one oxime 6-one 0-[2-(dimethylamino)ethyl]-                                             oxime                                                 g.   4-N,N-Dimethylsulfonamido-1,1a,                                                                  4-N,N-Dimethylsulfonamido-1,1a,                            6,10b-tetrahydrodibenzo[a,e]-                                                                    6,10b-tetrahydrodibenzo[a,e]cyclo-                         cyclopropa[c]cyclohepten-6-one                                                                   propa[c]cyclohepten-6-one 0-[2-                            oxime              (dimethylamino)ethyl]oxime                            h.   4-Methylthio-1,1a,6,10b-tetra-                                                                   4-Methylthio-1,1a,6,10b-tetra-                             hydrodibenzo[a,e]cyclopropa[c]-                                                                  hydrodibenzo[a,e]cyclopropa[c]-                            cyclohepten-6-one oxime                                                                          cyclohepten-6-one 0-[2-(dimethyl-                                             amino)ethyl]oxime                                     i.   4-n-Butoxy-1,1a,6,10b-tetra-                                                                     4-n-Butoxy-1,1a,6,10b-tetrahydro-                          hydrodibenzo[a,e]cyclopropa[c]-                                                                  dibenzo[a,e]cyclopropa[c]cyclo-                            cyclohepten-6-one oxime                                                                          hepten-6-one 0-[2-(dimethylamino)-                                            ethyl]oxime                                           __________________________________________________________________________

Dosage Forms

The antidepressant agents of this invention can be administered astreatment for psychiatric depression of the reactive and endogenoustypes by any means that produces contact of the active agent with theagent's site of action in the body of a mammal. In addition to theirantidepressant activity they also have a beneficial sedative action.They can be administered by any conventional means available for use inconjunction with pharmaceuticals; either as individual therapeuticagents or in a combination of therapeutic agents. They can beadministered alone, but are generally administered with a pharmaceuticalcarrier selected on the basis of the chosen route of administration andstandard pharmaceutical practice.

The dosage administered will, of course, vary depending upon knownfactors such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms, kind of concurrenttreatment, frequency of treatment, and the effect desired. Usually adaily dosage of active ingredient can be about 0.01 to 50 milligrams perkilogram of body weight. Ordinarily 0.05 to 40, and preferably 0.1 to 20milligrams per kilogram per day given in divided doses 2 to 4 times aday or in sustained release form is effective to obtain desired results.

Dosage forms (compositions) suitable for internal administration containfrom 2 milligrams to about 10 millgrams of active ingredient per unit.In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.01-90% by weight based onthe total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions; it can also be administeredparenterally, in sterile liquid dosage forms; or rectally in the form ofsuppositories.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, sucrose, mannitol, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compresses tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage froms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration contain preferably a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid either alone or combined aresuitable stabilizing agents. Also used are citric acid and its salts andsodium EDTA (ethylenediaminetetraacetic acid). In addition parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suppositories contain the active ingredient in a suitable oleaginous orwater-soluble base. The oleaginous class includes cocoa butter and fatswith similar properties; the water-soluble class includes polyethyleneglycols.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, E. W. Martin, a standard reference text to thisfield.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

Capsules can be prepared by filling standard two-piece hard gelatincapsules with the following mixture using conventional encapsulatingequipment:

    ______________________________________                                        Active ingredient     5       mg.                                             Lactose               125     mg.                                             Talc                  12      mg.                                             Magnesium stearate    3       mg.                                             ______________________________________                                    

Capsules

A mixture of active drug in soy bean oil is prepared and injected bymeans of a positive displacement pump in gelatin to form soft gelatincapsules containing 5 mg. of the active ingredient. The capsules arewashed in petroleum ether and dried.

Tablets

Tablets can be prepared by conventional procedures so that each unitwill contain:

    ______________________________________                                        Active ingredient     5       mg.                                             Spray dried lactose   150     mg.                                             Microcrystalline cellulose                                                                          35      mg.                                             Magnesium stearate    3       mg.                                             ______________________________________                                    

Parenteral

Parenteral composition suitable for intra muscular administration isprepared so that each ml. contains:

    ______________________________________                                        Active ingredient       5       mg.                                           Sodium carboxy methyl cellulose                                                                       .75     %                                             Polysorbate 80          0.04    %                                             Benzyl alcohol          0.9     %                                             Sodium chloride         0.9     %                                             Water for injection Q.S.                                                                              1       ml.                                           ______________________________________                                    

Suspension

An aqueous suspension is prepared for oral administration so that each 5mls. contain:

    ______________________________________                                        Active ingredient    5       mg.                                              Methylcellulose      5       %                                                Carboxy methyl cellulose                                                                           5       %                                                Syrup                30      %                                                Polysorbate 80       0.2     %                                                Sodium saccharin     2       mg.                                              Cherry flavor        0.1     %                                                Sodium benzoate      5       mg.                                              Water Q.S.           5       ml.                                              ______________________________________                                    

Use

A standard procedure for detecting and comparing the antidepressantactivity of compounds in this series for which there is good correlationwith human efficacy is the prevention of tetrabenazine-induced sedationand depression in mice. (Everett, "The Dopa Response Potentiation Testand Its Use in Screening for Antidepressant Drugs" pp. 164-167 in"Antidepressant Drugs" [Proceedings of the First InternationalSymposium) , S. Garattini and M. N. G. Dukes, eds., 1967.).

Groups of 10 Carworth CF₁ S female mice, 18-21 g. each, were fasted 1.5hours and were intubated with antagonist compounds at oral doses of 0,5, 25, and 125 mg/kg or 0, 1, 3, 9, 27, and 81 mg/kg in 0.20 ml of 1%Methocel (methylcellulose). The mice were challenged 30 minutes laterwith tetrabenzine (as the methane-sulfonate), 32 mg/kg intraperitoneally(dissolved in 0.20 ml. 0.05M KCl at pH 2.0). One hour after antagonist(30 minutes after tetrabenazine), the mice were examined for signs ofexploratory activity and ptosis (eyelid closure). Normal exploratoryactivity (relief from sedation) was recorded when a mouse was lifted bythe tail from a group of 10 in a testing box and placed on a stainlesssteel testing box lid (12.5 × 8 inches with 0.33 mesh) either turned itshead horizontally 30° in both directions or moved to the edge of thescreen within 10 seconds after being placed on the screen. Relief fromptosis was recorded when exactly 2 seconds after placing the mousefacing the observer, lid closure was less than 50% in both eyes. Thefollowing table gives results.

    ANTAGONISM OF TETRABENAZINE-INDUCED                                           DEPRESSION IN MICE ORALLY AT 1 HOUR POST-DRUG                                  ##STR22##                                                                    COMPOUND          ED.sub.50 (mg/kg) FOR PREVENTION OF                         R.sub.2                                                                            R.sub.1      EXPLORATORY LOSS                                                                          PTOSIS                                          __________________________________________________________________________    H CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                           2.3         0.4                                             H CH.sub.2 CH.sub.2 NH.sub.2 . HCl                                                              0.10        0.09                                            H CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                  15.6        9.0                                             H CH.sub.2 CH.sub.2 NHCH.sub.3                                                                  1.9         0.33                                            Cl                                                                              CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                           11.2        7.2                                             H CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 . HCl                                                     1.4         0.5                                             H CH.sub.2 CH.sub.2 NH.sub.2                                                                    0.25        0.09                                               ##STR23##      10.4        4.8                                             H                                                                                ##STR24##      3.0         1.0                                             H                                                                                ##STR25##      4.7         1.7                                             H  CH.sub.2 CH.sub.2 N[CH(CH.sub.3).sub.2 ].sub.2                                               5.2         3.3                                               amitriptyline ("ELAVIL")                                                                      4.7         1.7                                               imipramine ("TOFRANIL")                                                                       3.0         2.5                                                ##STR26##      6.5         3.2                                             __________________________________________________________________________

I claim:
 1. A pharmaceutical composition suitable for use as anantidepressant comprising a suitable pharmaceutical carrier and aneffective antidepressant amount of a compound of the formula ##STR27##where X or Y = H, F, Cl, Br, C₁₋ C₄ alkyl, C₁₋ C₄ alkoxy, CF₃, CH₃ S,CH₃ SO₂, SO₂ N(CH₃)₂, provided that one is H;Z = c₂₋ c₃ alkylene; R₁ andR₂ independently = H or C₁₋ C₄ alkyl; and its pharmaceutically suitablesalts.
 2. The pharmaceutical composition of claim 1 where R₁ and R₂ = Hor CH₃.
 3. The pharmaceutical composition of claim 1 where X and Y =H, Z= ethylene, and R₁ and R₂ = H or CH₃ ; and its hydrochloride salt. 4.The pharmaceutical composition of claim 3 where R₁ and R₂ = H.
 5. Thepharmaceutical composition of claim 3 where R₁ = H and R₂ = CH₃.
 6. Thepharmaceutical composition of claim 3 where R₁ and R₂ = CH₃.
 7. A methodof alleviating depression in a mammal which comprises administering tothe mammal an effective antidepressant amount of a compound of theformula: ##STR28## where X or Y = H, F, Cl, Br, C₁₋ C₄ alkyl, C_(1-C) ₄alkoxy, CF₃, CH₃ S, CH₃ So₂, SO_(2L) N(CH₃)₂, provided that one is H;Z =c₂₋ c₃ alkylene; R₁ and R₂ independently = H or C₁₋ C₄ alkyl; and itspharmaceutically suitable salts.
 8. The method of claim 7 where R₁ andR₂ = H or CH₃.
 9. The method of claim 7 where X and Y = H, Z = ethylene,and R₁ and R₂ = H or CH₃ ; and its hydrochloride salt.
 10. The method ofclaim 9 where R₁ and R₂ = H.
 11. The method of claim 9 where R₁ = H andR₂ = CH₃.
 12. The method of claim 9 where R₁ and R₂ = CH₃.